Synthesis of furoxan derivatives based on 4-aminofuroxan-3-carboxylic acid azide

Article abstract of DOI:10.1023/A:1026073108494

A convenient preparative method was developed for the synthesis of 4-amino-3-furoxancarboxylic acid azide, which is a universal synthon for the preparation of functional furoxan derivatives. This method was used for preparing new azo-, azoxy-, azido-, cyano-, nitro-, carbonylamino-, and hydroxylamino-substituted furoxan derivatives, which have earlier been difficultly accessible.

Full text of DOI:10.1023/A:1026073108494

1822
Russian Chemical Bulletin, International Edition, Vol. 52, No. 8, pp. 1822—1828, August, 2003
Synthesis of furoxan derivatives based
on 4ꢀaminofuroxanꢀ3ꢀcarboxylic acid azide
ꢀ
A. S. Kulikov, I. V. Ovchinnikov, S. I. Molotov, and N. N. Makhova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: mnn@ioc.ac.ru
A convenient preparative method was developed for the synthesis of 4ꢀaminoꢀ3ꢀ
furoxancarboxylic acid azide, which is a universal synthon for the preparation of functional
furoxan derivatives. This method was used for preparing new azoꢀ, azoxyꢀ, azidoꢀ, cyanoꢀ,
nitroꢀ, carbonylaminoꢀ, and hydroxylaminoꢀsubstituted furoxan derivatives, which have earꢀ
lier been difficultly accessible.
Key words: furoxans, azides, hydroxamic acids, azo and azoxy derivatives, oxidation,
nucleophilic substitution, dehydration, nitriles.
In recent years, the synthesis of new derivatives of
,2,5ꢀoxadiazole (furoxan) has attracted considerable atꢀ
pound 1 serves as a convenient substitute of extremely
unstable 3,4ꢀdiaminofuroxan, and each of the substituꢀ
8
1
tention. This interest stems largely from the fact that many
furoxan derivatives exhibit biological activities and, parꢀ
ticularly, from the ability of some of these derivatives to
serve as donors of nitrogen oxide.1 In addition, Nꢀ and
Oꢀcontaining derivatives of this heterocycle may be of
interest as potential components of gasꢀgenerating comꢀ
ents in the ring of 1 can be selectively transformed. In
addition, the azido group can be replaced by different
nucleophilic fragments (OH, OAlk, NH , etc.), which
2
—5
makes it possible to substantially extend the range of acꢀ
cessible compounds.
There are two approaches to the synthesis of comꢀ
pound 1, viz., the Curtius rearrangement of one of
two azidocarbonyl groups in diazide 2 and nitrosation
of 4ꢀaminofuroxanꢀ3ꢀcarboxylic acid hydrazide8 (3)
(Scheme 1). However, both methods cannot be considꢀ
ered as satisfactory. The first approach to the generation
of 1 is based on the difficultly accessible and explosive
potassium salt of dinitroacetic acid hydrazide (4), which
gives diazide 2 in low yield under the action of N O
6
,7
positions. 4ꢀAminofuroxanꢀ3ꢀcarboxylic acid azide (1)
and in some cases, its synthetic precursor, viz., furoxanꢀ
,4ꢀdicarboxylic acid diazide (2)) is one of the most conꢀ
(
3
,9
venient and universal synthons for the synthesis of many
functional furoxan derivatives.
Compound 1 contains two highly reactive functional
groups, viz., the amino and azidocarbonyl groups. The
amino group can be subjected to oxidation (to form nitro,
azo, and azoxy derivatives), alkylation, and acylation.
The azidocarbonyl group can serve as a precursor of the
amino group (Curtius rearrangement). In fact, comꢀ
2
4
through the intermediate formation of azidocarbonylꢀ
formonitrile oxide (5). Subsequently, diazide 2 is rather
smoothly transformed into the target compound 1 in
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1727—1733, August, 2003.
066ꢀ5285/03/5208ꢀ1822 $25.00 © 2003 Plenum Publishing Corporation
1

Synthesis of furoxan derivatives
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
1823
7
3% yield. The second approach is based on the use of
nucleophilic reagents. In particular, this enabled us to
prepare both free 4ꢀaminofuroxanꢀ3ꢀcarboxylic acid (10)
and its methyl (11) and ethyl (7) esters in high yields
(∼ 90%) by the reactions with Oꢀnucleophiles. The reacꢀ
tions of 1 with ammonia or hydrazine hydrate as nucleoꢀ
philes readily afforded amide 12 (in 92% yield) and hyꢀ
drazide 3 (in quantitative yield), respectively. Earlier,
amide 12 has been synthesized in low yield, but its charꢀ
acteristics, except for the melting point, have not been
reported. Hydrazide 3 was also prepared (see Scheme 1)
but in very low yield. Since these compounds were diffiꢀ
cultly accessible, investigations of their reactivities preꢀ
sented problems (Scheme 3).
monoethyl furoxanꢀ3,4ꢀdicarboxylate (6), which is transꢀ
formed into the corresponding acyl azide followed by the
Curtius rearrangement of the latter. In the latter process,
ethyl 4ꢀaminofuroxanꢀ3ꢀcarboxylate1 (7) is formed in a
yield of no higher than 6%. Compound 7 is successively
transformed into hydrazide 3 and then azide 1. Both methꢀ
ods afford the final product 1 in a total yield of no higher
than 2%.
To make compound 1 more accessible and simplify
the conditions for its preparation, we developed a new
scheme for the synthesis of diazide 2 followed by its transꢀ
formation into azide 1 according to a known reaction. We
demonstrated that the target azide 1 can be synthesized in
a total yield of 16% according to a rather short and simple
scheme by destructive nitration of readily available acetoꢀ
acetic ester11 giving rise to diethyl furoxanꢀ3,4ꢀdicarbꢀ
oxylate (8). The reaction of the latter with hydrazine
hydrate affords furoxanꢀ3,4ꢀdicarboxylic acid dihydrazide
0
1
2
Scheme 3
(
9), which is nitrosated to form 2 and then transformed
8
into the target azide 1 according to a known procedure.
It should be noted that the final azide 1 is synthesized
from ester 8 without isolation of intermediates, including
explosive diazide 2, which is generated and used in the
syntheses as a safe solution in CCl (Scheme 2).
4
Scheme 2
The ease of replacement of the azide group in 4ꢀaminoꢀ
3
ꢀazidocarbonylfuroxan (1) is manifested also in the reꢀ
actions with such Nꢀnucleophiles as hydroxylamine and
ꢀaminofuroxanꢀ3ꢀcarboxylic acid hydrazide (3), which
give rise to 4ꢀaminofuroxanꢀ3ꢀhydroxamic acid (13) and
,2ꢀbis(4ꢀaminoꢀ3ꢀfuroxanoyl)hydrazine (14), respecꢀ
4
1
tively, under mild conditions. The synthetic precursor of
azide 1, viz., diazide 2, reacts with hydroxylamine in a
similar way. In the latter case, both azido groups are reꢀ
placed to give furoxanꢀ3,4ꢀdihydroxamic acid (15) in high
yield. The latter synthesis was carried out with the use of
The more convenient procedure for the preparation of
azide 1 allowed us to make some furoxan derivatives,
which have been synthesized earlier, much more readily
accessible, study chemical transformations of both funcꢀ
tional groups in this compound in more detail, and synꢀ
thesize a series of new derivatives.
explosive diazide 2 as its safe solution in CCl (Scheme 4).
4
Since 4ꢀaminofuroxanꢀ3ꢀcarboxylic acid azide (1) is
easily accessible, we studied its reactions proceeding at
the amino group. Thus, the reactions of methoxycarbonyl
derivative 11 and 4ꢀaminoꢀ3ꢀhydroxymethylfuroxan (16),
1
4
Thus, the azido group in 1 is readily subjected to the
nucleophilic substitution under the action of various
which has been synthesized earlier, with a solution of
KMnO under the conditions generally used for the prepaꢀ
4

1824
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
Kulikov et al.
Scheme 4
hydride afforded the corresponding bis(nitroxymethyl)
derivative 23 (Scheme 6).
Scheme 6
ration of azo derivatives of furoxan13 led to smooth oxidaꢀ
tion of the amino group giving rise to the corresponding
azo derivatives 17 and 18 (Scheme 5).
Scheme 5
In addition to oneꢀelectron oxidation, we examined
the possibility of oxidation of 4ꢀaminofuroxanꢀ3ꢀcarboxꢀ
amide (12) by a twoꢀelectron oxidizing agent, viz., hydroꢀ
gen peroxide in sulfuric acid. It was found that under the
conditions used, oxidation of the amino group followed
two pathways to give a mixture of two products, viz.,
azoxy derivative 24 and nitro compound 25, in a ratio of
1 : 4. 4ꢀNitrofuroxanꢀ3ꢀcarboxamide (25), like 3,3´ꢀdiꢀ
carbamoylꢀ4,4´ꢀazofuroxan (19), was also subjected to
dehydration by phosphoric anhydride to produce 4ꢀnitroꢀ
furoxanꢀ3ꢀcarboxylic acid nitrile (26) in 60% yield. Earꢀ
For azo derivatives 19 13 and 20,15 which became much
more readily accessible, and new azofuroxan 18, selected
directions of their further transformations were also exꢀ
amined. For example, heating of 3,3´ꢀdicarbamoylꢀ4,4´ꢀ
azofuroxan (19) with phosphoric anhydride led to deꢀ
hydration of both amide groups to form the correspondꢀ
1
6
17
ing dinitrile 21, while in low yield. Earlier, compound 21
lier, the latter compound has been prepared in 28%
has been synthesized by oxidation to the azo derivative of
yield from the corresponding nitrolic acid (Scheme 7).
The yields of the newly synthesized compounds and their
physicochemical and spectroscopic characteristics are
given in Tables 1 and 2.
4
ꢀaminoꢀ3ꢀcyanofuroxan. Diazido derivative 22 was synꢀ
thesized by the reaction of 3,3´ꢀdinitroꢀ4,4´ꢀazofuroxan
20) with sodium azide through the nucleophilic displaceꢀ
(
ment of the nitro groups by the azido groups. The reaction
of azo derivative 18 with fuming nitric acid in acetic anꢀ
To summarize, we developed a rather simple preparaꢀ
tive procedure for the synthesis of 4ꢀaminofuroxanꢀ3ꢀ

Synthesis of furoxan derivatives
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
1825
Scheme 7
Nꢀnucleophiles, we synthesized a broad spectrum of new
furoxan derivatives containing the azo, azoxy, azido,
cyano, nitro, carbonylamino, hydroxylamino, and other
substituents. Earlier, these compounds, which are potenꢀ
tial biologically active compounds or components of
gasꢀgenerating compositions, have been difficultly acꢀ
cessible.
Experimental
The IR spectra were recorded on a URꢀ20 spectrometer in
KBr pellets. The UV spectra were measured on a Specord
UVꢀVIS spectrometer in MeOH. The NMR spectra were reꢀ
1
corded on Bruker WMꢀ250 ( H, 250 MHz) and Bruker AMꢀ300
1
3
14
(
C, 75.5 MHz; N, 21.5 MHz) spectrometers in the δ scale.
1
13
The H and C NMR chemical shifts were measured relative to
Me Si as the internal standard and the N NMR chemical
14
4
carboxylic acid azide (1), which is a universal synthon for
the preparation of functional furoxan derivatives. Based
on oxidative transformations of the amino group and
the reactions of the azidocarbonyl group with Oꢀ and
shifts were measured relative to MeNO as the external stanꢀ
2
dard. The mass spectra were obtained on a Varian MAT CHꢀ6
instrument. Thinꢀlayer chromatography was carried out on
Silufol UVꢀ254 plates.
Table 1. Selected physicochemical characteristics of the compounds synthesized
Comꢀ Yield
pound (%)
M.p./°C
Rf
(eluent)
Found
Calculated
Molecular
formula
(%)
C
H
N
1
3
1
1
1
1
1
1
1
1
2
2
2
2
16
100
90
91
93
75
40
78
62
79
90
12
12
46
129—130
lit. data : 129—130)
0.25
(CHCl3)
0.28
(PhH—MeOH, 10 : 1)
0.50
(EtOAc)
0.40
CHCl —EtOAc, 4 : 1)
8
(
*
260
22.23
22.65
24.29
24.84
29.82
30.20
25.47
25.01
25.22
25.51
25.53
3.31
3.17
2.22
2.08
3.55
3.17
2.90
2.80
2.22
2.52
2.23
2.11
—
44.20
44.02
28.72
28.98
26.17
26.41
38.35
38.88
35.49
35.00
39.02
39.16
—
C H N O
3
5
5
3
(
with decomp.)
130—131
0
C H N O
3 3 3
4
(
flash p.)
1
147—148
190—191
206—208
225—228
100—101
C H N O
4 5 3
4
(
3
2**
3
0.15
C H N O
3 4 4
3
(
CHCl —EtOAc, 4 : 1)
3
0.31
C H N O
3 4 4
4
(
СHCl —MeOH, 9 : 1)
3
4
—
C H N O
6 6 8
6
2
5.18
—
5
0.31
C H N O
4 4 4
6
(
t.expl.)
(СHCl —MeOH, 9 : 1)
3
7
139—141
111—112
121—123
0.47
CHCl3)
31.03
30.58
22.03
22.37
17.32
17.15
21.02
20.70
23.64
24.01
20.53
20.70
2.21
1.92
2.00
1.88
—
26.43
26.75
26.33
26.09
60.24
60.00
32.28
32.19
37.11
37.33
32.44
32.19
C H N O
8 6 6
8
(
8
0.33
C H N O
6 6 6
10
i
(
СHCl —Pr OH, 9 : 1)
3
2
0.43
(CHCl3)
0.26
CHCl3)
0.19
C N O
4 12 4
(
t.expl.)
3
136—138
1.12
1.16
1.70
1.34
1.31
1.16
C H N O
6 4 8
10
7
(
4
196—198
t.decomp.)
113—114
C H N O
6 4 8
(
(CHCl —EtOAc, 1 : 1)
3
5
0.25
C H N O
3 2 4
5
(
CHCl —EtOAc, 4 : 1)
3
*
*
The characteristics of compound 3 were not reported in the study.8
* For compound 12, only the melting point (205 °C) was given in the study.
1
2

1
826
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
Kulikov et al.
Table 2. Spectroscopic characteristics of the compounds synthesized
1
13
14
Comꢀ
pound
IR, ν/cm–1
(UV, λmax/nm)
H, [ C], { N} NMR
MS, m/z
(Irel (%))
Solvent
—
δ
3
3428, 3316, 1676, 1648, 1596, 1524,
—
—
1
1
7
480, 1348, 1308, 1228, 1196, 1104,
016, 972, 940, 876, 848, 812, 760,
28, 656
+
+
1
0
3425, 3330, 3250, 3178, 1750, 1732,
1
1
Acetoneꢀd6 6.45 (s, 2 Н, NH2)
145 [M ] (35), 115 [M – NO]
+
638, 1610, 1560, 1500, 1385, 1375,
230 (210, 267, 367)
(81), 101 [M – СО ] (100),
2
+
+
85 [M – 2 NO] (71), 71 [M
–
NO – СО ] (80)
2
1
1
1
1
2
3
3440, 3330, 3165, 3025, 2970, 2862,
711, 1615, 1525, 1442, 1368, 1238
211, 259, 367)
3423, 3405, 3320, 3210, 3180, 1684,
665, 1612, 1580, 1520, 1410, 1260
210, 254, 367)
3408, 3308, 3092, 1668, 1640, 1624,
DMSOꢀd6 3.90 (s, 3 H, Me);
6.35 (s, 2 Н, NH2)
—
1
(
DMSOꢀd6 6.50 (s, 2 Н, NH );
—
2
1
(
7.10 (s, 1 H, CONH);
8.47 (s, 1 H, CONH)
DMSOꢀd6 3.30 (br.s, 1 Н, ОН);
+
+
160 [M ] (8), 130 [M – NO] (24),
68 [furoxan ring] (100)
1
1
7
592, 1552, 1496, 1472, 1456, 1352,
216, 1108, 1040, 1008, 884, 860,
88, 768, 744, 684, 656
6.55 (s, 2 Н, NH );
2
10.50 (br.s, 1 Н, NH)
+
1
1
4
5
3468, 3428, 3320, 3176, 1692, 1660,
DMSOꢀd6 6.65 (s, 4 Н, 2 NH );
257 [M + 1 – NO] (7), 209
[M – 1 – 2 NO – NH ] (25),
187 [M + 1 – aminofuroxan]
(16), 144 [M /2 + 1] (17),
8 [furoxan ring] (100)
—
2
+
1
1
7
620, 1592, 1536, 1488, 1348, 1256,
204, 1120, 1012, 912, 856, 768,
08, 656
10.50 (br.s, 2 Н, 2 NH)
2
+
+
6
3572, 3412, 1708, 1558, 1476, 1424,
DMSOꢀd6 3.40 (br.s, 2 Н, 2 ОН);
10.30 (br.s, 2 Н, 2 NH)
DMSOꢀd6 [109.88 (C(3) of the ring);
1
9
328, 1284, 1204, 1096, 1052, 1024,
48, 892, 860, 792, 748, 700, 628
1
1
51.78 and 151.90 (2 СО);
53.81 (C(4) of the ring)]
1
1
7
8
2960, 1720, 1630, 1620, 1320, 1480
206, 256, 350)
3392, 2948, 2884, 1632, 1620, 1460,
Acetoneꢀd6 3.91 (s, 6 Н, 2 Me)
—
—
(
DMSOꢀd6 4.10 (s, 2 Н, 2 ОН);
4.60 (s, 4 Н, 2 СН2)
1
1
404, 1372, 1292, 1240, 1136, 1052,
032, 944, 844,760, 728, 692, 616
+
+
2
2
2
3
2205, 2135, 1580, 1510, 1460, 1345,
225, 1090, 1055, 1030, 860, 805, 760
3020, 2908, 1640, 1620, 1496, 1468,
Acetoneꢀd6 [125.65 (C(3) of the ring); 280 [M ] (4), 224 [M – 2 N ] (7),
2
+
1
150.20 (C(4) of the ring)] 192 [M – 2 NO – N ] (100)
2
CDCl3
CDCl3
5.65 (s, 4 Н, 2 СН2)
—
1
1
6
448, 1420, 1380, 1312, 1280, 1156,
056, 1008, 944, 848, 768, 756, 744,
80, 612
{–50.6 (CONO )}
2
+
+
2
4
3440, 3412, 3284, 3224, 3180, 1712,
DMSOꢀd6 7.88 (s, 1 H, CONH);
8.33 (s, 1 H, CONH);
300 [M ] (2), 270 [M – NO] (7),
257 [M – Н NСO + 1] (19),
227 [M – Н NСO – NO] (2),
+
1
1
1
692, 1620, 1600, 1520, 1496, 1464,
376, 1316, 1256, 1156, 1072, 1036,
012, 924, 828, 800, 752, 736, 720
2
+
8.39 (s, 1 H, CONH);
8.53 (s, 1 H, CONH)
2
+
184 [M – 2 Н NСO – NO + 2]
2
DMSOꢀd6 [105.9 (C(4) of the ring);
(8), 159 [Н NСO – ring – NO +
2
1
1
06.1 (C(4) of the ring);
53.1 (СО); 154.4
1] (3), 129 [Н NСO – ring + 1]
2
(10), 113 [Н NСO – ring – О + 1]
2
(
(
C(4) of the ring); 155.6
C(4) of the ring)]
(22), 84 [furoxan ring.] (24),
44 [N O] (100)
2
DMSOꢀd6 {66.1 (NNO)}
DMSOꢀd6 8.23 (s, 1 Н, CONH);
8.54 (s, 1 H, CONH)
2
5
3448, 3304, 3284, 3184, 1700, 1640,
564, 1512, 1452, 1400, 1340, 1028
213, 245)
—
1
(
Acetoneꢀd6 {–277 (Nring, ∆ν1/2
50 Hz); –36.1 (NO2,
ν1/2 = 11.5 Hz)}
=
1
∆

Synthesis of furoxan derivatives
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
1827
Furoxanꢀ3,4ꢀdicarboxylic acid diazide (2) and 4ꢀaminoꢀ
precipitate that formed was filtered off, washed with water, and
dried in air.
furoxanꢀ3ꢀcarboxylic acid azide (1). A solution of diethyl furoxanꢀ
1
1
3
,4ꢀdicarboxylate (23 g, 0.1 mol) in MeOH (80 mL) was added
1,2ꢀBis(4ꢀaminofuroxanꢀ3ꢀcarbonyl)hydrazine (14). Azide 1
(1.70 g, 0.01 mol) was added to a solution of hydrazide 3 (1.59 g,
0.01 mol) in a minimum amount of DMSO. The reaction mixꢀ
ture was stirred until the starting azide 1 was consumed (accordꢀ
ing to the TLC data). The white precipitate that formed was
filtered off, washed with water and acetone, and dried in air.
Since the compound is virtually insoluble in organic solvents, its
dropwise to a mixture of 85% hydrazine hydrate (25 mL,
.42 mol), MeOH (80 mL), and water (50 mL) at –20 °C for
5 min. The reaction mixture was stirred at the same temperaꢀ
ture for 1 h, after which concentrated HCl (80 mL) was added
0
4
dropwise for 30 min and then a solution of NaNO (32 g) in
2
water (160 mL) was added for 30 min. The reaction mixture was
13
kept at –20 °C for 1 h, extracted with CCl (3×40 mL), washed
C NMR spectrum was not measured and a satisfactory chroꢀ
4
with water (3×40 mL), dried with MgSO , and concentrated on
matogram was not obtained.
4
a rotary evaporator at a temperature of no higher than 30 °C to a
volume of no less than 40 mL. Dioxane (40 mL) and water
Furoxanꢀ3,4ꢀdicarbohydroxamic acid (15). A solution of
NH OH•HCl (2.8 g, 0.04 mol) neutralized with NaHCO
2
3
(
1.5 mL) were added to the resulting solution (containing
(3.36 g, 0.04 mol) in a minimum amount of water was added to a
∼
4.9 g of diazide 2). The reaction mixture was rapidly heated to
solution containing diazide 2 (∼ 2.24 g, ∼ 0.01 mol) in CCl . The
4
8
0 °C, stirred for 10 min, and cooled. Then water (60 mL) was
reaction mixture was stirred for ∼ 3—4 h until the starting diazide
was consumed (according to the TLC data, R 0.67, CHCl as
added dropwise. The precipitate that formed was filtered off,
f
3
washed with water, and dried in air. Compound 1, which was
identical with the product prepared earlier, was obtained in a
the eluent) and then cooled to ∼ 0 °C. The precipitate that formed
was filtered off, washed with a small amount of ice water and
8
yield of 2.72 g.
CCl , and dried in air.
4
4
ꢀAminofuroxanꢀ3ꢀcarboxylic acid hydrazide (3). Water
3,3´ꢀBis(methoxycarbonyl)ꢀ4,4´ꢀazofuroxan (17). Methyl
ester 11 (8.48 g, 0.053 mol) was dissolved in acetone (207 mL) at
35 °C. Concentrated HCl (310 mL) was rapidly added with coolꢀ
(
80 mL) and hydrazine hydrate (6.5 g, 0.13 mol) were added to
azide 1 (10.2 g, 0.06 mol) wetted with dioxane. The reaction
mixture was stirred at ∼ 20 °C for 1 h. The precipitate that formed
was filtered off, washed three times with water, and dried in air.
Compound 3 was prepared in a yield of 9.5 g.
ing and vigorous stirring. Then a solution of KMnO (72 g) in
4
water (1100 mL) was added dropwise at 20 °C (cooling), the
reaction mixture was stirred at 20 °C for 2.5 h, and MnO that
2
Methyl 4ꢀaminofuroxanꢀ3ꢀcarboxylate (11). A solution of
NaOH (2.36 g, 0.059 mol) in MeOH (20 mL) was added dropwise
to a suspension of azide 1 (10 g, 0.059 mol) in MeOH (50 mL) at
precipitated was dissolved by adding oxalic acid. The product
was filtered off and dissolved in AcOH (200 mL) at 55 °C. After
cooling to 20 °C, the reaction mixture was diluted with water
(200 mL) for 20 min. The precipitate was filtered off, washed
with 40% AcOH and water, and dried in air.
∼
20 °C for 10 min and the reaction mixture was stirred for 10 min.
The product was filtered off and washed three times with water.
An additional amount of the product was obtained from the
mother liquor by distilling off the methanol. The latter portion
of the product was washed with water and combined with the
main portion, after which the product was dried in air.
3,3´ꢀBis(hydroxymethyl)ꢀ4,4´ꢀazofuroxan (18). A solution
of KMnO (2.91 g, 0.0184 mol) in water (50 mL) was added
4
1
4
dropwise to a solution of 4ꢀaminoꢀ3ꢀhydroxymethylfuroxan 16
(2.41 g, 0.0184 mol) in concentrated HCl (24 mL) and CH Cl
2
2
Ethyl 4ꢀaminofuroxanꢀ3ꢀcarboxylate (7) was prepared analoꢀ
gously to compound 11 in 91% yield. Its characteristics are
identical with those of the product prepared earlier.1
(10 mL) at a temperature of no higher than 20 °C. The reaction
mixture was stirred for 15 min. Then oxalic acid was added until
MnO2 was consumed. The solution was saturated with NaCl
(35 g) and extracted with EtOAc (3×20 mL). The extracts were
0
4
ꢀAminofuroxanꢀ3ꢀcarboxylic acid (10). A solution of NaOH
7.71 g, 0.118 mol) in water (40 mL) was added dropwise to a
suspension of azide 1 (10 g, 0.059 mol) in water (107 mL) at
20 °C. The reaction mixture was stirred for 5 min, after which
dilute H SO was added dropwise to pH 7. Then the reaction
(
dried with MgSO and the solvent was distilled off. After drying
4
in a vacuum desiccator over P O , a resinous product was obꢀ
2
5
∼
tained. An analytically pure sample was prepared by flash chroꢀ
i
matography on 5/40 µm silica gel (Pr OH—CHCl , 1 : 9, as the
2
4
3
mixture was stirred for 5 min and a solution of NaNO (4.07 g)
eluent).
2
in water (10 mL) was added dropwise. After 5 min, anhydrous
Na SO (13.5 g) was added and the reaction mixture was stirred
3,3´ꢀDicyanoꢀ4,4´ꢀazofuroxan (21). A suspension of 3,3´ꢀdiꢀ
1
3
carbamoylꢀ4,4´ꢀazofuroxan (19) (1 g, 0.0035 mol) and P O
2
4
2
5
for 20 min. The product was filtered off, washed two times with
(2.8 g, 0.020 mol) in tetrachloroethane (10 mL) was heated with
stirring to 100 °C and kept at this temperature for 1 h. Then
CHCl3 (20 mL) was added and the reaction mixture was reꢀ
fluxed for 5 min. The organic layer was decanted away. The
cold water, and dried in a vacuum desiccator over P O . Cauꢀ
2
5
tion: The compound is sensitive to mechanical treatment; it exꢀ
plodes upon grinding with a porcelain pestle in a porcelain mortar.
4
ꢀAminofuroxanꢀ3ꢀcarboxamide (12).
A
concentrated
residue was extracted with boiling CHCl (2×20 mL). The exꢀ
3
NH OH solution (20 mL) was added in one portion to a suspenꢀ
tracts were combined and filtered through a layer of 40/100 µm
silica gel (the diameter was 25 mm, the height of the layer was
15 mm). The solvent was concentrated until a dense suspension
was obtained. The product was filtered off, washed on a filter
with CHCl3 (one time), and dried in air. Compound 21 was
prepared in a yield of 15 mg (1.7%). Its characteristics are idenꢀ
4
sion of azide 1 (10.2 g, 0.06 mol) in water (100 mL) at ∼ 20 °C
and the reaction mixture was stirred for 40 min. The precipitate
that formed was filtered off, washed with water, and dried in air.
4
ꢀAminofuroxanꢀ3ꢀcarbohydroxamic acid (13). Azide 1
(
(
1.70 g, 0.01 mol) was added to a solution of NH OH•HCl
2
1
6
1.05 g, 0.015 mol) neutralized with NaHCO (1.26 g, 0.015 mol)
tical with those of the product synthesized earlier.
3
in water (15 mL). The reaction mixture was stirred until the
azide was consumed (according to the TLC data). The color of
the suspension gradually changed from yellow to white. The
4,4´ꢀDiazidoꢀ3,3´ꢀazofuroxan (22). Sodium azide (0.78 g,
0.012 mol) was added with stirring to a solution of 3,3´ꢀdinitroꢀ
4,4´ꢀazofuroxan (20) (0.29 g, 0.001 mol) in AcOH (15 mL).
1
5

1828
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
Kulikov et al.
After 48 h, the precipitate that formed was filtered off and washed
with water. An additional amount of the product was isolated
from the mother liquor by adding water (10 mL). The total yield
was 0.25 g.
This study was financially supported in part by the
International Science and Technology Center (ISTC,
Grant 11882) and NATO (Grant SST CLG 977566).
3
,3´ꢀBis(nitroxymethyl)ꢀ4,4´ꢀazofuroxan (23). Nitric acid
–
3
References
(
d = 1.51 g cm ) (5.9 mL, 0.141 mol) was added dropwise to
Ac O (20 mL) at 0—5 °C and then a solution of diol 18 (1.83 g)
2
in AcOH (2 mL) was added. The reaction mixture was poured
into an ice—water mixture (100 g), a resinous substance being
formed on the walls of the beaker. The aqueous phase was deꢀ
canted away and the resinous substance was dissolved in EtOAc
1. H. Bohn, J. Brendel, P. A. Martorana, and K. Schonafinger,
Brit. J. Pharm., 1995, 114, 1605.
2. A. Gasco, R. Fruttero, and G. Sorba, IL Pharmaco, 1996,
51, 617.
(
2×20 mL). The solvent was evaporated in vacuo. The residue
3. H. Cerecetto, R. Di Maio, M. Gonzalez, M. Risso, P. Saenz,
G. Seoane, A. Denicola, G. Peluffo, C. Quijano, and
C. OleaꢀAzar, J. Med. Chem., 1999, 42, 1941.
4. D. Boschi, C. Cena, A. Di Stilo, R. Fruttero, and A. Gasco,
Bioorg. Med. Chem., 2000, 8, 1727.
was stirred with CHCl (10 mL) for 5 min. The yellow precipiꢀ
tate that formed was filtered off and washed with CHCl (5 mL).
The product was purified by flash chromatography. For this
purpose, the precipitate was dissolved in CH Cl (60 mL), filꢀ
3
3
2
2
tered through a layer of 5/40 µm silica gel (the diameter was
6 mm, the height of the layer was 26 mm) on a Schott funnel,
and washed out with CH Cl (40 mL). The solvent was concenꢀ
5. M. Li, F. Siꢀshen, and L. G. Mei, Chem. Pharm. Bull., 2000,
48, 808.
6. A. B. Sheremetev, I. L. Yudin, N. N. Makhova, I. V.
Ovchinnikov, and D. B. Lempert, Proc. of 33rd Int. Annual
Conf. of ICT (June 25—28, 2002), Karlsruhe (Germany),
128 (1—12).
7. A. B. Sheremetev, I. L. Yudin, S. M. Aronova, I. V.
Ovchinnikov, and N. N. Makhova, Tez. dokl., Vseross. konf.
"Energeticheskie kondensirovannye sistemy" [Abstrs. of Papers,
AllꢀRussian Conf. on Energetic Condensed Systems],
(Chernogolovka, October 28—31, 2002), YanusꢀK, Moscow,
2002, 104 (in Russian).
8. I. V. Ovchinnikov, A. N. Blinnikov, N. N. Makhova, and
L. I. Khmel´nitskii, Mendeleev Commun., 1995, 58.
9. N. N. Makhova, A. S. Kulikov, A. N. Blinnikov, I. V.
Ovchinnikov, T. S. Pivina, V. P. Lebedev, T. S. Konkova,
and E. A. Arnautova, Proc. of 30rd Int. Annual Conf. of ICT
(June 29—July 2, 1999), Karlsruhe (Germany), 58 (1—12).
10. N. N. Makhova, A. N. Blinnikov, and L. I. Khmel´nitskii,
Mendeleev Commun., 1995, 56.
3
2
2
trated in vacuo. The product was transferred to a filtering funnel,
washed two times with CHCl , and dried in air. Paleꢀyellow
3
crystals were obtained in a yield of 385 mg. An additional amount
of the product (15 mg) was isolated from the mother liquor.
4
ꢀNitrofuroxanꢀ3ꢀcarboxamide (25) and 3,3´ꢀdicarbamoylꢀ
4
,4´ꢀazoxyfuroxan (24). Concentrated H SO (45 mL) and then
2
4
CCl (45 mL) were added dropwise to 85% hydrogen peroxide
4
(
45 mL) at 15 °C. Then amide 12 (12.0 g, 0.083 mol) was added
in one portion. The reaction mixture was stirred at 20 °C for 1 h,
during which it turned green. After 30 min, the reaction mixture
turned yellow. Then the reaction mixture was diluted with ice
water (135 mL) and a layer of CCl was separated. The aqueous
4
layer was extracted with EtOAc (5×60 mL) and washed with
water (2×45 mL). Ethyl acetate was evaporated in vacuo. The
residue was diluted with water (50 mL) and stirred until the oil
that formed solidified. The precipitate was filtered off and dried
in a vacuum desiccator over P O . A mixture of compounds 24
2
5
and 25 was obtained in a yield of 10.35 g. To isolate compound
5, the mixture of the compounds was dissolved in EtOAc
20 mL) at 40 °C, CHCl (80 mL) was added, and the precipiꢀ
tate that remained undissolved was filtered off. This operations
was repeated three times. The combined mother liquors were
concentrated to dryness and dried in air to prepare compound
11. L. Bouveault and A. Bongert, Bull. Soc. Chim. Fr., 1902,
27, 1164.
12. G. Tennant and G. M. Wallace, J. Chem. Soc., Chem.
Commun., 1982, 267.
13. I. V. Ovchinnikov, A. S. Kulikov, N. N. Makhova, P. Tosco,
A. Di Stilo, R. Fruttero, and A. Gasco, Il Farmaco, 2003, 58
(in press).
2
(
3
2
5. The undissolved product was washed one time with the
same mixture of the solvents and dried in air to prepare comꢀ
pound 24.
14. A. N. Blinnikov, A. S. Kulikov, N. N. Makhova, and L. I.
Khmel´nitskii, Izv. Akad. Nauk, Ser. Khim., 1996, 1782 [Russ.
Chem. Bull., 1996, 45, 1692 (Engl. Transl.)].
3
ꢀCyanoꢀ4ꢀnitrofuroxan (26). A mixture of amide 25 (4.57 g,
0
.036 mol) and P O (3.89 g) was heated on an oil bath (the bath
15. I. V. Ovchinnikov, N. N. Makhova, L. I. Khmel´nitskii,
V. S. Kuz´min, L. N. Akimova, and V. I. Pepekin, Dokl.
Akad. Nauk, 1998, 359, 499 [Dokl. Chem., 1998, 359, 67
(Engl. Transl.)].
16. V. G. Andrianov, Khim. Geterotsikl. Soedin., 1997, 1115
[Chem. Heterocycl. Compd., 1997, 33, 973 (Engl. Transl.)].
17. O. A. Rakitin, V. A. Ogurtsov, E. A. Khaibullina, T. I.
Godovikova, and L. I. Khmel´nitskii, Khim. Geterotsikl.
Soedin., 1993, 1283 [Chem. Heterocycl. Compd., 1993, 29,
1099 (Engl. Transl.)].
2
5
temperature was 140—160 °C) in vacuo (1—5 Torr). The prodꢀ
uct was distilled off into a trap cooled with an acetone—solid
CO2 mixture for 30 min. The crude product was sublimed in
vacuo (20—30 Torr) using a waterꢀaspirator pump at 75 °C to
prepare the product in a yield of 3.37 g. Then the product was
dissolved in CH Cl (4 mL), CCl (4 mL) was added, and the
mixture was concentrated on a rotary evaporator at ∼ 20 °C until
a dense suspension was obtained. The precipitate was filtered
off, washed on a filter with CCl (1.5 mL), and dried in air to
2
2
4
4
prepare compound 26 in a yield of 2.71 g (48%). The characterꢀ
istics of 26 are identical with those of the product synthesized
earlier.17
Received March 11, 2003;
in revised form April 25, 2003